Method for stereo-chemical equilibration of secondary carbinamines



Patented Aug. 26, s 1952 i .i t 3 METHOD FOR STEREO-CHEMICAL EQUILI-BRATION OF SECONDARY QARBINAMINES Thomas Carl Aschner, Philadelphia,Pa., assignor to Smith, Kline & French Laboratories, Philadelphia, Pa.,a corporation of Pennsylvania No Drawing. Application August 31, 1949,

Serial No. 113,487

This invention relates to a method for the stereochemical equilibrationof optical isomers of secondary carbinamines, that is to say compoundswhere the nitrogen linked carbon atom is a cen- 6 Claims. (01. 260570.8iI

2 I The nitrogen linked carbon atom is a center of asymmetry.

R and R are unlike and selected from the group consisting of alkyl,aryl, substituted aryl,

ter of asymmetry. i 5 aralkyl, substituted aralkyl, aralkanol, substi- Ituted aralkanol, isocyclic, heterocylic, isocyclo- -o*- alkyl,heterocycloalkyl radicals and the remainder of a ring system of whichthe nitrogen linked carbon is a member. It W111 be understood that theterm t More specifically, the method according to this 131011 315 usedherein Will 6011110118 partial or cominvention is applicable tosecondary carbinamines ,plete interconversion of spacial arrangement ofhaving th following structure: the substituents of a secondary carbonatom linked to a nitrogen atom. The method in accordance with thisinvention will be useful for RJ LY effecting partial or completeracemization of optical isomers, including both enantiomorphs andwherein diastereoisomers, and partial or complete inter- Y is a nitrogencontaining radical of which conversion of geometrical isomers, where insuch the nitrogen is the linking atom to carbon isomers the spacialarrangement of the nitrogen atom, selected from the group consisting fatom and the hydrogen atom around a secondary amino, monoamylaminohaving not more than 8 carbon atom is in part or completely responsiblecarbon atoms, phenylalkylamino having not more for the lsomensm 0f the kthan 10 carbon atoms and an imino radical hav- Thusg by of m the methoding not more than 10 carbon atoms the nitrogen according to thisinvention is applicable to the linked carbon atom is a center ofasymmetry. partial or complete racemization of optical isoand R and areunlike and selected f m mers Primary a d Secondary ammes 1n Whlch groupconsisting of alkyl having not more than the amino group is linked to atleast one second- 3 carbon atoms, ,cycloalkyl having carbon Myasymmetllc P atom, a d schifi's [bases atoms, phenyl, phenylalkyl, thealkyl portion of (N-substituted aldimines or ketl in which which has notmore than 8 carbon atoms, all of the mirosen 1s lmked a Smgle bond 1 anwhich groups may contain substitutents selected asymmetrlc Q f f atom;Pnmary from the group consisting of alkyl having not Secondary ammes 1nWhlch the nitrogen is more than 8 carbon atoms, cycloalkyl having notlink d & a Secondary carbpll atom Which is part more than 6 carbonatoms, alkoxy having not of a ring system and Wh are u p i of more than8 carbon atoms, hydroxy and alkylexisting i 0 and trans isomers, may beinteramino having not more than 8 carbon atoms. converted. By way offurther illustration of the appli- Refer nce may be d t an a t by Doermecability of the method according to this inven- & Aschner appe in J01117191 0f the American tion, the method will be found applicable forthe Chemic S y. 833, dated March 1949, for 40 equilibration of, forexample, stereo isomers of further explanation of the term equilibrationth following compounds; as used herein.

By way of example, the method in accordance %'pfieny%'hyqroxy'z'methylammopropane with this invention is applicable tooptically active gfizfl j f gg gmg secondary carbmamines having thestructure. 5 1 (p methy1pheny1) 2 aminopmpane R l-phenyl-l-aminoethane1-phenyl-l-ethylaminoethane EiI 1-cyclohexy1-2-aminopropane1-cyclohexyl-2-methylaminopropane wherein 2-amino-6-methy1heptane Y is anitrogen-containing radical, of which 2-methylamino-6-methylheptane thenitrogen is the linking atom to the carbonN-(beta-phenylisopropyl)-beta-ph atom, selected from the groupconsisting of ketimine amino, monosubstituted amino and imino radi-Cis-l-amino-2-methy1cyclohexane cals. J. r l-amino-phenyl-ethaneGenerally speaking, the method in accordance with this inventioninvolves the treatment of optically active secondary carbinamines of thetype indicated to reversibly establish a double bond between theasymmetric secondary carbon atom and the adjacent nitrogen atom. Uponestablishing such a double bond, the carbon and nitrogen atoms, it isbelieved, become coplanar and the original, specific spacial arrangementof substituents around the secondary carbon atom is thereby destroyed.Having established such a double bond, a single bond is reestablishedbetween the secondary carbon atom and the adjacent nitrogen by theaddition of hydrogen to the carbon atom.

The hydrogen atom may add to the secondary carbon atom in either of twopossible spacial positions, thus giving rise to two stereolsomers invarious proportions. The precise proportion will depend upon theparticular compounds treated.

Thus, it is believed that the method in accordance with this inventioninvolves eifecting a com pletely or partially reversible hydrogentransfer between a carbon tc-nitrogen single bond and acarbon-to-nitrogen double bond either intramoleoularly orinterinolecularly, depending upon the starting compounds used and uponthe con ditions of treatment.

More specifically, the method inaccordance with this invention involvesequilibrating optically active secondary carbinami-nesof the typeindicated by heating at about atmospheric, or greater, pressu e, either:in a batch or a continuous flow system, with a hydrogenation ordehydrogenation catalyst; such as, for example, nickel, palladium,platinum, cobalt, Raney nickel, or other hydrogenation catalyst known tothe art. It is to be particularly noted that other hydrogenation ordehydrogenation catalysts, as a class, may be utilized for equilibrationof carbinamines according to the method of. this inven tion with equalapplicability to those specifically disclosed herein. Thus, thisinvention is not to be considered as being limited to utilization o onlythose catalysts mentioned.

Proceeding in accordance with the method various temperatures may beused, depending upon the particular catalyst and the particular compoundtreated. Generally speaking a temperature within the range 100 :300 C.will be eifective using a nickel catalyst.

It is believed that reactions by which the hydrogen transfer indicatedabove may take place will be illustrated by the following:

In the above reactions it will be understood that R -R will be as givenabove for R and R in connection with the general formula and that thenitrogen linked carbon is a center of asymmetry.

In the treatment a solvent will be used where the compound to be treatedis not liquid at the temperature employed.- Where thecompound to betreated is a liquid, the use of" solvent is. not

4 necessary. Variously, it will be advantageous to proceed with thetreatment in an atmosphere of inert gas, for example, nitrogen, ammoniagas, or the like.

Variously the initial addition of small amounts of an imine such asproduced in the reaction A above may be found to be advantageous,although generally not necessary inasmuch as an amine of the generalformula above may be slowly dehydrogenated to the imine by the proceduresuggested in reaction A above.

The following examples of procedure according to the method of thisinvention for the equilibration of specific compounds will make apparentthe general applicability of the method for the equilibration ofsecondary carbinamines of thetypes indicated.

XAMPLE 1 Racemz'zatz'on oj Z-2-aim'no-fi-methylheptane 20 gms. of1-2-amino-G-methyl-heptane possessing an optical rotation a =+0.3 washeated in the presence of 2 gms. of nickel pellets at a temperature ofC. for four hours to yield, upon decantation, of the reaction mixturefrom the catalyst and subsequent fractionation, a 2-amino-6-methylheptane fraction of a substantially decreased rotation.

Following the above procedure the following compounds will bee'quilibrated:

(a) d or l-2-amino-6-methylheptane (b) I-Z-amin'o'butane (c)d-2-aminode'cane' (:1) d or 1-2-amino-5-dimethyl'aminopentane EXAMPLE 2-R'a'cemization of d-Z-cycZohexyZ-Z-methylami'nopropane I CH2 t CH;CH-CHz-OH-CH3 CH CH NH-CH:

EXAMPLE 3 Racemizatz'on of dertro-phenylisopropylaminkz Thedextro-rotatory optical isomer of phenylisopropylamine may be racemizedto a mixture of the levo and dextro rotatory isomers by the methoddisclosed in this invention. According to this method, 100 grams of thedextro isomer are treated with 5 grams of Raney nickel catalyst at atemperature of C. for a period of six The reaction is carried out in anat'-' mosphere of nitrogen gas at 1.1 atmospheres of pressure.

Upon decantation of the residual liquid and fractionation thereof, thereis recovered phenylisopropylamine showing only 8% of its originaloptical activity, in good yield.

Proceeding as above d or l-l-(p-methylphenyl) -l-amino-2-(p-methoxyphenyl) ethane will be equilibrated.

EXAMPLE 4 Racemization of Zero-phenylisopropylamine ([1115 cm-m-nm Theracemizatlon of the levo isomer of phenylisopropylamine to a d1 mixturewill be accomplished by a procedure identical with that in Example 3except that an equivalent amount of 1- phenylisopropylamine will be usedin place of the dextro isomer.

It may also be accomplished through utilization of a continuous flowsystem by which 1,000 grams of l-phenylisopropylamine are passed througha catalytic chamber in which is contained 100 grams of nickel onkieselguhr pellets maintained at a temperature of 135 C. over a periodof 3 /2 hours at atmospheric pressure. Fractionation of the resultingliquid phase from this operation yielded phenylisopropylamine showing12% of its original optical activity.

EXAMPLE 5 Racemz'zation of dextro-phenylisopropylmethylamine The dextrorotatory isomer of phenylisopropylmethylamine will be racemized to a d,lmixture by the method disclosed in this invention. According to thismethod 100 grams of d-phenyl-isopropylmethylamine are treated with gramsof the catalytic material comprising nickel on kieselguhr which ismaintained at a temperature of 145 C. The reaction may be carried out atatmospheric pressure and over a period of 10 hours.

Upon fractionation of the liquid decanted from the reaction mixturethere is obtained in good yield phenylisopropylmethylamine having onlyof the original optical activity.

Proceeding as above d or l-l-(p-methylphenyl) -2-methylaminopropaneethane will be equilibrated.

EXAMPLE 6 Racemz'zation of d-N-(fi-phenylisopropyl) 3-phenylisopropylidenimine The dextro isomer of N-(,8'-pheny1isopropyl)-fi-phenylisopropyl ketimine may be prepared'by reactingdextro-B-phenylisopropyl amine with an equimolar quantity ofp-phenylacetone by a method known to the art.

The resultant dextro rotatory ketimine will be racemized by the methodaccordin to this invention in which grams of the dextro isomer is heatedwith 10 grams of nickel on kieselguhr pellets at C. temperature for aperiod of 5 hours. There is obtained upon fractionation of the decantedreaction mixture the N-(pY-phenyl isopropyl) -/3-phenyl isopropylketimine in excellent yield, possessing only a fraction of its originaloptical activity.

Acid hydrolysis of the resulting ketimine permits one to obtainphenylisopropylamine exhibiting a correspondingly low degree of opticalr0- tation.

What is claimed is:

1. The method of equilibrating a secondary carbinamine having thestructure:

wherein Y is a nitrogen containing radical, of which the nitrogen is thelinking atom to the carbon atom, selected from the group consisting ofamino, monoalkylamino, phenylalkylamino and an imino radical; thenitrogen linked carbon atom is a center of asymmetry; and R and R areunlike and selected from the group consisting of alkyl, cycloalkyl,phenyl, phenyalkyl, which comprises heating a secondary carbinaminehaving said structure in the presence of a catalyst selected from thegroup consisting of nickel, Raney nickel, palladium, platinum andcobalt.

2. The method of equilibrating an optical isomer ofl-phenyl-Z-aminopropane which comprises heating an optical isomer oflaphenyl-2-aminopropane in the presence of a catalyst selected from thegroup consisting of nickel, Raney nickel, palladium, platinum andcobalt.

3. The method of equilibrating an optical isomer of1-phenyl-2-methylaminopropane which comprises heating an optical isomerof l-phenyl- Z-methylaminopropane in the presence of a catalyst selectedfrom the group consisting of nickel, Raney nickel, palladium, platinumand cobalt.

4. The method of equilibrating an optical isomer of 19(p-methylphenyl) 2aminopropane which comprises heating an optical isomer of B-(p-methylphenyl)-2-aminopropane in the presence of a catalyst selectedfrom the group consisting of nickel, Raney nickel, palladium, platinumand cobalt.

5. The method of equilibrating an optical isomer ofl-2-amino-6-methylheptane which comprises heating an optical isomer ofl-Z-amlno-B-methylheptane in the presence of a catalyst selected fromthe group consisting of nickel, Raney nickel, palladium, platinum andcobalt.

6. The method of equilibrating an optical isomer ofd-l-cyclohexyl-Z-methylaminopropane which comprises heating an opticalisomer of d-l-cyclohexyl-2-methylaminopropane in the presence of acatalyst selected from the group consisting oi nickel, Raney nickel,palladium, platinum and cobalt.

THOMAS CARL ASCHNER.

No references cited.

1. THE METHOD OF EQUILIBRATING A SECONDARY CARBINAMINE HAVING THESTRUCTURE: